Diabetes 4.4% by 2030, compared with 2.8% in

          Diabetes mellitus describes a series of hyperglycemia-related diseases that are caused by insulin resistance, excessive glucagon secretion, or insufficient insulin secretion. Many people with pre-diabetes are unaware of their disease, particularly when the symptoms are mild. The symptoms of type 2 diabetes mellitus (T2DM) are generally milder than those of type 1 diabetes mellitus (T1DM). The symptoms of both T1DM and T2DM include polydipsia, increased hunger, polyuria, blurred vision, and a dry mouth.  Symptoms specific to more advanced TIDM are nausea, vomiting, and weight loss, whereas the symptoms of T2DM might include those of its chronic complications like neuropathic pain or numbness in the feet and legs, recurrent yeast infections and poor wound healing.   1.1.2 Prevalence of DM         The prevalence of diabetes varies according to the disease subtype, but it is becoming increasingly common over time. One study predicted that the prevalence of diabetes worldwide could rise to 4.4% by 2030, compared with 2.8% in 2000 1. The mortality rate of Bahraini due to diabetes was 3.4% in 1988.  Diabetes mellitus has turned out to be a standout amongst the most widely recognized general medical issues in the nation. A people group based investigation among moms matured 18 to 48 years demonstrated that 8.5% of them had diabetes. Lack of physical exercise and poor food habits may contribute to increasing the prevalence of diabetes 2.  Preparing of doctors in the administration of diabetes, epidemiological studies, and wholesome assessment of local food are among the most critical measures expected to control diabetes in Bahrain. In December 2011, six of the main 10 nations with the most noteworthy pervasiveness of diabetes (in grown-ups matured 20 to 79 years) are in the Middle East: Bahrain (19.9%) (International Diabetes Federation, 2011). The prevalence of diabetes in Bahrain was 15.6% in 2015, compared to 15.4% in 2012 3. The main purpose to understand the causes of the rapid increase of diabetes prevalence in order is to suggest efficient actions susceptible to reduce risk of diabetes in the Arab countries. The frequency of individual types of diabetes is discussed in more detail below. 1.1.3 Diagnosis and monitoring of diabetes           Diabetes is diagnosed based on criteria that were first proposed in 1997 1 and later modified in 2003 4. These are consistent with related diagnostic criteria of American Diabetes Association 5. Patients with diabetes generally monitor their own disease course using blood glucose measurements, which allow them to alter diet according to the body’s needs. In addition, physicians monitor the progress and management of the disease by measuring the levels of hemoglobin A1c (HBA1c), which provides an indicator of glucose control over a period of three months period. 1.1.4 Types of diabetes1.1.4.1 Type 1 diabetes          T1DM (type 1 diabetes mellitus or insulin-dependent diabetes mellitus), occurs when the autoimmune-mediated destruction of pancreatic ?-cells leads to inadequate insulin secretion. This insulin deficiency can lead to various conditions, including hyperglycemia and ketoacidosis 6. Approximately 5% to 10% of all cases of diabetes are T1DM, although the incidence varies significantly among countries. Finland and Sardinia were reported to have the highest incidence of T1DM (37 cases/100,000 people/year), whereas Venezuela and China have the lowest incidence (0.1 cases/100,000 people/year) 7.  The global incidence of T1DM has been rising rapidly since the 1960s 8. Type 2 diabetes (T2DM)1. Epidemiology            T2DM is a metabolic disease that can be defined according to the major symptoms of insulin resistance and high blood sugar concentrations. It is by far the most prevalent form of diabetes. It is caused by progressive insulin resistance and the dysfunction of pancreatic ?-cells 8. The World Health Organization (WHO) revealed that the global incidence of T2DM rose from 108,000,000 in 1980 to 422,000,000 in 2014, with 8.5% of adults affected by this debilitating disease (http://www.who.int/diabetes/global-report/en/). Further, the WHO predicts that diabetes is likely to be the 7th-most common cause of global mortality by 2030. Uncontrolled T2DM leads to hyperglycemia, which can injure the nervous system, eyes, heart and blood vessels, and kidneys. It is a significant source of both kidney failure and blindness 8, 9. There are a number of management strategies for patients with T2DM. Because it is a progressive condition, T2DM can be delayed or even prevented with appropriate screening, dietary interventions, and increased physical activity 10. Causes           There are two main causes of T2DM: lifestyle factors, and a genetic origin. Much of the elevated prevalence of T2DM over time is thought to be due to the rising prevalence of a high-fat “Western” diet and reduced physical activity, which together have increased the global incidence of obesity dramatically. The hereditary nature of T2DM is complex, although it is clear that the offspring of a parent with T2DM have an increased disposition toward developing the disease. The number of genes linked with a causative role in T2DM development has increased over time and includes TCF7L2, ADAMTS9, NOTCH2, CDC123/CAMK1D, and JAZF1 9. The role of pancreatic ?-cells in the pathogenesis of T2DM          Until relatively recently, insulin resistance was considered to be the primary driving force behind the development of T2DM. However, increasing evidence has revealed the importance of pancreatic ?-cell dysfunction. For example, a decreased ?-cell mass, impaired insulin secretion, and several mutations in ?-cell specific genes were reported. The reduced ?-cell mass is likely caused by increased ?-cell apoptosis associated with inflammation, increased fatty acid and glucose levels, endoplasmic reticulum stress, and protein misfolding 11.  Although it remains a matter of debate, some researchers and endocrinologists believe that ?-cell defects, rather than insulin resistance, are the major driving force in T2DM Risk factors for T2DM          There are both genetic- and lifestyle and disease-related risk factors for T2DM. Genetic risks include a family history of T2DM and ethnicity; the prevalence of T2DM is significantly higher in African American, Hispanic, and Asian individuals compared with Caucasians 13. Lifestyle-related risks include a poor diet and a sedentary lifestyle. Individuals with certain diseases also have an increased susceptibility to T2DM, such as pre-diabetes (diminished glucose tolerance and impaired fasting glucose levels), PCOS (polycystic ovarian syndrome), androgen deficiency in males, metabolic syndrome, and obesity Other types of diabetes1. ?-cell genetic defects         Maturity-onset diabetes of the young (MODY) describes a family of hereditary autosomal-dominant types of diabetes. It accounts for 1–5% of diabetes cases in the USA 15. Some patients with MODY have no signs or symptoms and are diagnosed during the screening of a relative with MODY or when high glucose is detected during routine checkups. Other patients present with the typical symptoms of diabetes, such as hyperglycemia, polyuria, and polydipsia. At least 13 different genetic causes are currently known, although MODY2 and MODY3, which are caused by mutations in glucokinase and HNF1A, respectively, are the most frequent 15. Genetic defects of insulin action        Insulin receptor (IR) mutations are associated with several metabolic abnormalities, which could be hyperglycemia, hyperinsulinemia, or overt diabetes. IR mutations have been linked to pancreatic diseases, including pancreatic cancer, infection, pancreatectomy, pancreatitis, and trauma. In addition, several hormones including adrenaline, growth hormone, glucagon, and cortisol, precipitate a state of hyperglycemia by inhibiting the actions of insulin. As such, the abnormal elevation in these hormones seen in acromegaly, glucagonoma (a rare ?-cell tumor), Cushing’s syndrome, and pheochromocytoma often result in secondary diabetes Complications of DM1.15.1 Diabetic Ketoacidosis (DKA)        DKA is an acute, major, life-threatening complication of diabetes that mainly occurs in patients with T1DM, but it is not uncommon in some patients with T2DM.It is characterized by a positive urinary acetone test, breath with a fruity, sweet odour and hypoglycaemia.  DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine) Hyperosmolar hyperglycemic state         One of the most serious and conceivably hazardous complexities associated with diabetes is a hyperosmolar hyperglycemic state (HHS); also known as a diabetic non-ketotic hyperosmolar coma (DNKHC)., significant glycosuria and hypoglycemia (plasma glucose >600 mg/dL) without deep, labored breathing, and an elevated plasma osmolality of >320 mOsm/kg with no ketoacidosis 18. Most cases occur in elderly patients, and it has a mortality rate of 10–20%. It is caused by dehydration or reduced fluid intake, often as a result of a concomitant illness. HHS is treated by normalizing the hyperglycemia and hyperosmolality, balancing electrolytes, and replenishing fluids; treating the underlying illness is also important. Microvascular complications          The diabetes-associated microvascular complications are diabetic retinopathy, neuropathy, and nephropathy. There is an increased risk of these complications according to the extent and interval of hyperglycemia; therefore, treatment involves restoring normoglycemia. Diabetic retinopathy, which occurs when blood vessels at the rear of the retina become damaged by the high glucose concentrations, is the most common diabetic microvascular complication and the most frequent cause of blindness globally 19. The symptoms are altered vision, which can manifest as blurred vision, floaters in the eye, vision loss, and dark spots in the visual field. If left untreated it can lead to glaucoma, retinal detachment, or even blindness. The American Diabetes association defines diabetic neuropathy (DN) as diabetes together with the presence of signs/symptoms of peripheral nerve dysfunction; it can be autonomic, motor, sensory, focal, or diffuse. It is caused by glucose-induced nerve damage, which can lead to symptoms such as numbness, sharp pain, muscle weakness, and a tingling or burning sensation. If left untreated, it can lead to amputations 20. DN is defined by microalbuminuria (30–299 mg albumin excretion in 24-h) followed by proteinuria (>500mg in 24-h). Without treatment, the disease typically progresses from microalbuminuria to proteinuria to impaired kidney function and end stage renal disease requiring dialysis or kidney transplant. It is very common, and up to 7% of T2DM patients may exhibit microalbuminuria at diagnosis 19. It occurs when high glucose concentrations damage the kidneys and lead to the presence of protein in the urine. It is asymptomatic in the early stages and is only diagnosed when protein is detected in the urine. In addition to normalizing blood sugar, treatment involves lowering blood pressure with anti-hypertensives 19. Macrovascular complications          The major macrovascular complications of diabetes are stroke, peripheral artery disease, and coronary artery disease. All three conditions are preceded by chronic inflammation-induced atherosclerosis, which leads to narrowing of the arteries, although the mechanisms that lead to diabetes enhancing the propensity of patients forming atherosclerotic plaques are poorly understood. Macrovascular complications are associated with the highest diabetes-associated expenditure and the leading cause of diabetes-induced deaths 21. Furthermore, diabetes is a risk factor and predictor of coronary artery disease, stroke, and cerebrovascular disease. Although improving glycemic control might not reduce the incidence of macrovascular complications, decreasing hypertension and using lipid-lowering agents could decrease the risk 19. 1.2 C-peptide1.2.1 Identification       The connecting peptide (C-peptide) consists of a short 31-amino-acid protein which connects insulin’s A-chain to its B-chain in the proinsulin molecule; it was first discovered in 1967 22, 23. It is produced during the biosynthesis of insulin as a product of proinsulin. Proinsulin, which contains the A and B chains of insulin that are linked by C-peptide, is created by ?-cells of the pancreas as a single chain polypeptide. In the Golgi apparatus, proinsulin is packaged into ?-granules and is then proteolytically processed to remove C-peptide and leave the A and B chains of insulin, which are linked by disulfide bonds in the mature peptide. Equimolar amounts of the two mature hormones are stored in secretory granules in ?-cells before releasing into the circulation via the liver.        Estimation of C-peptide is important to know the difference between insulin produced by the body and insulin injected into the body. The pancreas starts off as a large molecule that splitting into insulin and C-peptide 24. Insulin and C-peptide are primarily secreted when glucose concentrations change, and secretion can be enhanced by nutritional factors such as amino acids and free fatty acids. A number of proteins and hormones regulate this process, including glucagon-like peptide-1 (GLP-1), leptin, melatonin, growth hormone (GH), and estrogen 25. Insulin secretion requires secretory granules to fuse with the plasma membrane, followed by exocytosis to release insulin and C-peptide. The secretion is biphasic in humans: a transient secretion that lasts for ~10 minutes and peaks at 1.4 nmol/min when plasma glucose levels are ~7 mM, followed by a second phase of secretion at ~0.4 nmol/min 26.         C-peptide testing forms an important part of diabetes care. C-peptide serves as a marker for understanding or monitoring insulin secretion, and C-peptide testing remains an important tool in the management of patients with diabetes. For example, it can be used to help distinguish T1DM from T2DM and MODY because equimolar amounts of insulin and C-peptide are produced and secreted. As such, reduced C-peptide levels are indicative of insufficient insulin secretion and hence T1DM. Furthermore, several reports revealed that the combination of C-peptide and insulin sufficiency could promote the development and progression of diabetic complications 15 .In T2DM patients and cases of hypoglycemia, C-peptide value was important to know if the insulin is still being produced by the body 27. C-peptide values are based on the blood sugar level. Low values (or no insulin C-peptide) indicate that your pancreas is producing little or no insulin 28 .          Measuring C-peptide is measured rather than insulin for several reasons. First, insulin cannot be used as an accurate marker of insulin secretion in patients receiving exogenous insulin injections or those that produce autoantibodies against insulin itself. Second, the insulin secreted into the portal vein is metabolized hepatically, whereas C-peptide is not 29. Third, C-peptide has a much longer half-life than insulin (~30 min vs. ~5 min) in healthy individuals; therefore, circulating C-peptide levels are around five-times higher 30. Interpretation of C-peptide levels must be with alert in renal failure.  Roughly 50% of C-peptide delivered is evacuated by the kidneys, the lion’s share of which is debased by means of peritubular take-up with around 5% of aggregate C-peptide created discharged unaltered in the urine. Consequently, large amounts of C-peptide can be dishonestly raised where there is renal failure 28. 1.2.2 Functions of C-peptide         Although initial research led to the belief that C-peptide was an inert peptide produced during insulin processing, data now suggest that it has a number of important biological effects. For example, C-peptide activates a number of calcium-dependent intracellular signaling pathways, including phospholipase-C? (PLC?), extracellular-regulated kinases (ERKs), nuclear factor-?B (NF?B), Rho GTPases, protein kinase C (PKC), and peroxisome proliferator-activated receptor-? (PPAR?). This then upregulates the activity of Na+K+ ATPases and endothelial nitric oxide synthase (eNOS) 28, 31. These effects might be exerted through binding between C-peptide and GPR146 (an orphan GPCR) 32. 1.2.3 Anti-inflammatory effects of C-peptide        It exerts a number of anti-inflammatory impacts in smooth muscle cells (SMCs) by modulating a number of intracellular signaling pathways. Vascular SMCs (VSMCs) exhibit important functions in atherosclerotic plaque formation and vascular diseases. They are also critical for extracellular matrix (ECM) formation since they produce proteoglycans, connective tissues such as elastic fibers, and collagens. Growth factors including platelet-derived growth factor (PDGF) activate VSMCs; they then migrate to areas of inflammation, where they begin to proliferate. The inflammatory NF-?B pathway plays several key roles in the development of atherosclerosis. After activation, the p65 subunit of NF-?B is detected in VSMCs, endothelial cells, and macrophages, as well as in atherosclerotic lesions (in both the atheromatous regions and in intima-media that has thickened due to fibrosis). In VSMCs, the presence of high glucose concentrations activates NF-?B, which stimulates VSMC proliferation 33. NF-?B also modulates inflammatory signaling pathways and apoptosis in VSMCs. For example, elevated glucose levels activate p38 mitogen- activated protein kinase (MAPK) and NF-?B signaling followed by important inflammatory cytokines, AP-1, fractalkine, and monocyte chemotactic protein type 1 (MCP-1) 34. Importantly, these effects could be reversed when the p38 MAPK pathway is inhibited by PPAR?. Taken together, these data indicate that the activation of NF-?B in VSMCs has a critical function in diabetes-associated vascular disease; therefore, treatments or preventative agents that target NF-?B signaling are receiving increasing attention. It applies anti-inflammatory impacts in several models of inflammation-induced vascular injury. Monocytes follow and relocate into the subendothelial space, which is a critical step in the development of atherogenesis. C-peptide can affect the interaction between endothelial cells and circulating monocytes. For example, Luppi et al. revealed that that C-peptide secured against high glucose-instigated endothelial dysfunction via a number of anti-inflammatory mechanisms. Specifically, C-peptide treatment inhibited NF-?B activation, reduced adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) levels. C-peptide administration additionaly decreased the adherence of U-937 myeloid cells and HAEC cells and reduced the secretion of proinflammatory cytokines, such as MCP-1 and interleukin-8 (IL-8) 35.            Diabetic vasculopathy (DV) is caused by hyperglycemia, which leads to organ-specific complications caused by defective blood vessels. These complications can be macrovascular (for example, stroke or myocardial infarction) or microvascular (such as retinopathy, nephropathy, or neuropathy) 36. Data suggest that the reduced circulating C-peptide and insulin concentrations play an important role in DV 37. Similar to (DN),